Adrenergic receptors mediate physiological responses to the catecholamines, norephinephrine and epinephrine, and are members of the superfamily of G protein-coupled receptors having seven transmembrane domains. These receptors, which are divided pharmacologically into α-1, α-2 and β-adrenergic receptor types, are involved in diverse physiological functions including functions of the cardiovascular and central nervous systems. The α-adrenergic receptors mediate excitatory and inhibitory functions: α-1 adrenergic receptors are typically excitatory post-synaptic receptors which generally mediate responses in an effector organ, while α-2 adrenergic receptors are located postsynaptically as well as presynaptically, where they inhibit release of neurotransmitters. The α-adrenergic receptors also mediate vascular constriction. Agonists of α-2 adrenergic receptors currently are used clinically in the treatment of hypertension, glaucoma, spasticity, and attention-deficit disorder, in the suppression of opiate withdrawal, as adjuncts to general anesthesia and in the treatment of cancer pain.
α-2 adrenergic receptors are present in various bodily organs, including eyes and nose. It is believed that they play a role in nasal congestion, among many other diseases.
α-2 adrenergic receptors are presently classified into three subtypes based on their pharmacological and molecular characterization: α-2 A/D (α-2A in human and α-2D in rat); αa-2B; and α-2C (Bylund et al., Pharmacol. Rev. 46:121-136 (1994); and Hein and Kobilka, Neuropharmacol. 34:357-366 (1995)). The α-2A, α-2B, and α-2C subtypes appear to regulate arterial and/or venular contraction in some vascular beds, and the α-2A and α-2C subtypes mediate feedback inhibition of norepinephrine release from sympathetic nerve endings.
Many compounds having selective α-2 agonist activity are known and include brimonidine (which has been used for lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension), guanfacine (which has been used to control high blood pressure), dexmedetomidine (which has been used as a sedative, analgesic, sympatholytic and anxiolytic), and methyl dopa (which has been used as a centrally-acting adrenergic antihypertensive).
Nasal conditions, such as nasal congestion, cause inconvenience and suffering to many individuals. The use of conventional decongestant nasal sprays cause rebound congestion, often lasting 24 hours or longer, which typically results after using these sprays for more than three consecutive days, or even after a single day's use. In addition, continued use of conventional nasal decongestants (such as Afrin®, Afrin is a registered trademark of MSD Consumer Care, Inc.; Dristan®, Dristan is a registered trademark of Wyeth LLC; and many others) may result in chronic and long term inflammatory pathological conditions. These conditions frequently occur as a subject attempts to reverse the rebound congestion with more and more frequent use of the conventional nasal decongestant. Phenylephrine, a strong α-1 agonist, and oxymetazoline, a strong α-1 agonist with some α-2 agonist activity, are powerful nasal decongestants. However, these decongestants are associated with numerous side effects upon repeat use. Rhinitis medicamentosa is one such result side effect that results from inflammatory ischemic changes caused by such patterns of use. Rhinitis medicamentosa ultimately results in a total nasal blockage which may not be relieved by simply stopping the medication. It may take days, weeks, months, or even medical or surgical intervention to treat rhinitis medicamentosa. It is currently estimated that 10 million people in the U.S. alone suffer from this condition.
It is a long held dogma of prior art that all topical α-agonists when used nasally induce vasoconstriction, and as a result, cause ischemia. Thus, it is thought that all topical α-agonists, when repeatedly topically applied to mucosal surfaces, result in rebound hyperemia and/or congestion, tachyphylaxis, and chronic ischemic inflammatory change, such as rhinitis medicamentosa.
Thus, there is a need in the art for new compositions and methods that would be useful for treatment of nasal conditions, including but not limited to nasal congestion, which cause long lasting relief with no or only transient (i.e., only a few hours, with very low incidence) rebound congestion and no rhinitis medicamentosa. There is also a need for new formulations for medications useful for the treatment of nasal congestion, whereby said medications can be administered through the nasal route to relieve nasal congestion on a regular basis without significant rebound congestion and/or rhinitis medicamentosa.